Insights into the phylogeny and coding potential of microbial dark matter
Open accessAbstract
Genome sequencing enhances our understanding of the biological world by providing blueprints for the evolutionary and functional diversity that shapes the biosphere. However, microbial genomes that are currently available are of limited phylogenetic breadth, owing to our historical inability to cultivate most microorganisms in the laboratory. We apply single-cell genomics to target and sequence 201 uncultivated archaeal and bacterial cells from nine diverse habitats belonging to 29 major mostly uncharted branches of the tree of life, so-called ‘microbial dark matter’. With this additional genomic information, we are able to resolve many intra- and inter-phylum-level relationships and to propose two new superphyla. We uncover unexpected metabolic features that extend our understanding of biology and challenge established boundaries between the three domains of life. These include a novel amino acid use for the opal stop codon, an archaeal-type purine synthesis in Bacteria and complete sigma factors in Archaea similar to those in Bacteria. The single-cell genomes also served to phylogenetically anchor up to 20% of metagenomic reads in some habitats, facilitating organism-level interpretation of ecosystem function. This study greatly expands the genomic representation of the tree of life and provides a systematic step towards a better understanding of biological evolution on our planet. Uncultivated archaeal and bacterial cells of major uncharted branches of the tree of life are targeted and sequenced using single-cell genomics; this enables resolution of many intra- and inter-phylum-level relationships, uncovers unexpected metabolic features that challenge established boundaries between the three domains of life, and leads to the proposal of two new superphyla. Currently available genome sequences give us a narrow view of the remarkable diversity of microorganisms because the vast majority of them have never been cultivated in pure culture. Here Tanja Woyke and colleagues use single-cell genomics to target and sequence 201 uncultivated archaeal and bacterial cells from nine diverse habitats. This information reveals numerous intra- and inter-phylum relationships and a number of unexpected metabolic features. On the basis of the new data the authors propose taxonomic revisions to the archaeal and bacterial domains, including a proposal to reorganizing the Archaea into three superphyla.
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Metagenomics has provided the scientific community with access to approximately 99% of organisms that are yet to be cultured.
“Metagenomics has started to provide the scientific community with access to the ∼99% of organisms that are yet to be cultured (50).”
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Koonin, E. V. (2015) · Philosophical Transactions of the Royal Society B: Biological Sciences · doi:10.1098/rstb.2014.0333 · Cited by 145 · see citing works
Biology of a widespread uncultivated archaeon that contributes to carbon fixation in the subsurface
Probst, A. J., Weinmaier, T., Raymann, K., Perras, A., Emerson, J. B., Rattei, T., Wanner, G., Klingl, A., Berg, I. A., Yoshinaga, M., et al. (2014) · Nature Communications · doi:10.1038/ncomms6497 · Cited by 135 · see citing works
Sporulation, bacterial cell envelopes and the origin of life
Tocheva, E. I., Ortega, D. R., & Jensen, G. J. (2016) · Nature Reviews Microbiology · doi:10.1038/nrmicro.2016.85 · Cited by 121 · see citing works
Early Microbial Evolution: The Age of Anaerobes
Martin, W. F., & Sousa, F. L. (2016) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a018127 · Cited by 129 · see citing works
Advancements toward a systems level understanding of the human oral microbiome
McLean, J. S. (2014) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2014.00098 · Cited by 108 · see citing works
Metabolic independence drives gut microbial colonization and resilience in health and disease
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Press, M. O., Wiser, A. H., Kronenberg, Z. N., Langford, K. W., Shakya, M., Lo, C.-C., Mueller, K. A., Sullivan, S. T., Chain, P. S. G., & Liachko, I. (2017) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/198713 · Cited by 103 · see citing works
Phylogenetic Signal, Congruence, and Uncertainty across Bacteria and Archaea
Martinez-Gutierrez, C. A., & Aylward, F. O. (2021) · Molecular Biology and Evolution · doi:10.1093/molbev/msab254 · Cited by 95 · see citing works
ATP synthase evolution on a cross-braced dated tree of life
Mahendrarajah, T. A., Moody, E. R. R., Schrempf, D., Szánthó, L. L., Dombrowski, N., Davín, A. A., Pisani, D., Donoghue, P. C. J., Szöllősi, G. J., Williams, T. A., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-42924-w · Cited by 86 · see citing works
“Despite the wide distribution of ATP synthases across cellular life, ouranalysesrevealedthatmanyDPANNArchaeaandCPRBacteriamay have minimal complexes, as is the case in the DPANN Nanoarchaeum equitans 86 , or even lack all genes for an ATP synthase complex (Fig.”
BackgroundInfluentialPhelps, C. M., Willis, N. B., Duan, T., Lee, A. H., Zhang, Y., Rodriguez J, D. M., Pandey, S. P., Laughlin, C. R., Rosen, A. B. I., McPherson, A. C., et al. (2025) · Cell · doi:10.1016/j.cell.2025.06.018 · Cited by 91 · see citing works
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Genomic insights into the uncultivated marine <i>Zetaproteobacteria</i> at Loihi Seamount
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Self-citationNew substitution models for rooting phylogenetic trees
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“We considered a concatenated alignment of 16S and 23S rRNA sequences sampled from across the known diversity of Archaea, including the Euryarchaeota, ‘TACK’ superphylum [45], and recently described ‘DPANN’ lineages [38].”
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A multi-modal deep language model for contaminant removal from metagenome-assembled genomes
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Arnoux, J. (2026) · Thèse de doctorat, Université Paris-Saclay / PPanGGOLiN · doi:10.70675/eee354d9zf63dz48ebz9444zd1809f8fb74d
- Authors
- Rinke, C., Schwientek, P., Sczyrba, A., Ivanova, N. N., Anderson, I. J., Cheng, J.-F., Darling, A., Malfatti, S., Swan, B. K., Gies, E. A., Dodsworth, J. A., Hedlund, B. P., Tsiamis, G., Sievert, S. M., Liu, W.-T., Eisen, J. A., Hallam, S. J., Kyrpides, N. C., Stepanauskas, R., Rubin, E. M., Hugenholtz, P., & Woyke, T.
- Affiliations
- Joint Genome Institute (US)
- University of Technology Sydney (AU)
- Bigelow Laboratory for Ocean Sciences (US)
- University of British Columbia (CA)
- University of Nevada, Las Vegas (US)
- University of Patras (GR)
- Woods Hole Oceanographic Institution (US)
- University of Illinois Urbana-Champaign (US)
- University of California, Davis (US)
- The University of Queensland (AU)
- Corresponding author
- Hugenholtz, Philip
- Woyke, Tanja
- ORCID
- Rinke, Christian
- Schwientek, Patrick
- Sczyrba, Alexander
- Ivanova, Natalia N.
- Cheng, Jan-Fang
- Darling, Aaron
- Malfatti, Stephanie
- Swan, Brandon K.
- Dodsworth, Jeremy A.
- Hedlund, Brian P.
- Sievert, Stefan M.
- Liu, Wen-Tso
- Eisen, Jonathan A.
- Hallam, Steven J.
- Kyrpides, Nikos C.
- Rubin, Edward M.
- Hugenholtz, Philip
- Woyke, Tanja
- Venue
- Nature
- Published
- 2013-07-14
- Volume
- 499
- Issue
- 7459
- Pages
- 431-437
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2166123725
- Cited by
- 2,394
- References
- 52
- Citations by year
- 2026: 90 · 2025: 156 · 2024: 159 · 2023: 194 · 2022: 163 · 2021: 197 · 2020: 242 · 2019: 190 · 2018: 210 · 2017: 197 · 2016: 208 · 2015: 190 · 2014: 149 · 2013: 42
- FWCI
- 88.02
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Nature (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Open Access Server of the Woods Hole Scientific Community (Woods Hole Scientific Community) (submittedVersion, cc-by-nc-sa)
- eScholarship (California Digital Library) (submittedVersion)
- UTS ePRESS (University of Technology Sydney) (submittedVersion)
- PUB – Publications at Bielefeld University (Bielefeld University) (submittedVersion)
- VBN Forskningsportal (Aalborg Universitet) (submittedVersion)
- Funders
- National Science Foundation (DEAC02-05CH11231, 1232982, 1136727, 1136488, 0452333)
- U.S. Department of Energy (-AC02-05CH11231, Contract No. DE-AC02-05-CH11231, 05CH11231, No. DE-AC02-05-CH11231, DE AC02 05CH11231, DE-AC02-)
- National Aeronautics and Space Administration (DE-AC02-05CH11231, NNX11AR78G, EXO-NNX11AR78G)
- Alfred P. Sloan Foundation (DE-AC02-05CH11231)
- Woods Hole Oceanographic Institution
- University of Nevada, Las Vegas
- Canadian Institute for Advanced Research
- Tula Foundation
- Joint Genome Institute (AC02-05CH11231, DE–AC02–05CH11231)
- Bundesministerium für Bildung und Forschung (DE-AC02-05CH11231)
- Office of Science (No. DE-AC02- 05-CH11231, DEAC02–05CH11231, AC02-05CH11231, DE-AC02, 05CH11231, Contract No. DE-AC02-05CH11231)
- Natural Sciences and Engineering Research Council of Canada (DE-AC02-05CH11231)
- Australian Research Council (DP120103498)
- British Columbia Knowledge Development Fund
- Office of International Science and Engineering
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Physical Sciences › Environmental Science › Ecology › Microbial Community Ecology and Physiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protist diversity and phylogeny
- Keywords
- microbial dark matter, unculturable microorganisms, single-cell genomics, phylogenetic relationships, three domains of life, microbial diversity, taxonomic revision
- MeSH terms
- Archaea, Bacteria, Molecular Sequence Data, Phylogeny, Genome, Bacterial, Sequence Analysis, DNA, Ecosystem, Genome, Archaeal, Metagenome, Metagenomics, Single-Cell Analysis
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